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Brady R 0, Gal A E, Bradley R M, Martensson E, Warshaw A L & Laster L
Enzymatic defect in Fabry’s disease: ceramidetrihexosidase deficiency.
N. Engi. J. Med. 276:1163-7, 1967.
[Lab. Neurochem. Nati. Inst. Neurological Dis. and Blindness, and Sect. Gastroenterol.
Metabolic Dix. Branch, Nati. Inst. Arthritis and Metabolic Dix., NIH, Bethesda, MDI
Fabry’s disease is an inherited metabolic disorder
irs which a lipid called ceramidetrihexoside accumulates throughout the body. The condition
was shown to be due to a deficiency of the enzyme that catalyzes the hydrolytic cleavage of
the terminal molecule of galactose of ceramidetrihesoside. [The SCI~indicates that this paper has
been cited in over 290 publications since 1967.1
Roscoe 0. Brady
Developmental and Metabolic
Neurology Branch
National Institute of Neurological
and Communicative Disorders and Stroke
National Institutes of Health
Bethesda, MD 20205
July 5, 1984
“Fabry’s disease is transmitted as an X-chromosome-linked recessive disorder. Hemizygous males
frequently have a reddish-purple maculopapular
rash on their skin. They experience acroparesthesias in the hands and feet that get worse with exercise and hot weather. The clinical picture is further
characterized by corneal opacities, tortuosity of
retinal vessels, generalized atherosclerosis, propensity to premature myocardial infarction and
stroke, and eventual renal shutdown. Heterozy.
gotes usually have much milder manifestations
although severe signs may be apparent in occasional individuals.
“Original descriptions of this condition
1 were pub2
lished by dermatologists W. Anderson and J. Fabry
in 1898. Eventually, it became apparent that there
was ageneralized accumulation of lipid in the tissue
of these patients. In 1963, Charles C. Sweeley and
Bernard Klionsky reported that ceramidetrihesoside
[galactosylgalactosylglucosylceramide, (CTH)] was
3
the major accumulating material in Fabry’s disease.
Much of this lipid appears to be derived from glycolipids in the stronsa of senescent erythrocytes.
“In 1965 and 1966, David Shapiro, julian N.
Kanfer, and I synthesized several sphingolipids
II
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labeled with C with which the metabolic defects
in Gaucher’s disease and Niemann-Pick disease
were established. Based on these findings, I anticipated that Fabry’s disease was caused by a deficiency of an enzyme that cleaves
the terminal mol4
ecule of galactose from CTH. However, in 1966, it
was not possible to synthesize CTH chemically
with a radioactive tracer in the critical terminal
molecule of galactose. Andrew E. Gal joined my
group and succeeded in labeling ceramidetrihesoside throughout the molecule by exposing it to
radioactive hydrogen gas in a sealed vessel (the
Wilebach procedure). Since (he terminal galactose
contained radioactive 3H, we were able to trace
the fate of this moiety. We discovered that mammalian tissues contain an enzyme that catalyzes
the hydrolytic cleavage of this galactose and that
intestinal
5 mucosa had the highest activity in this
regard. Optimal conditions for measuring the activity of this enzyme were determined and lactosylceramide was identified as the product of the
reaction. When this information became available, Andrew 1. Warshaw and Leonard Laster obtained biopsy specimens of human small intestinal
mucosa from 12 controls, from men with Fabry’s
disease, and from the mother of one of the patients. Ceramidetrihexosidase activity was readily
demonstrated in the specimens from the controls,
whereas no activity was detected in the biopsies
from the men with Fabry’s disease. The activity of
the enzyme in the sample from the female carrier
was 25 percent of the mean of the controls,a value
considerably less than might have been expected
for a heterozygote, but compatible with the Lyon
hypothesis for X-chromosome inactivation. Furthermore, this level of enzyme activity was consistent with her clinical presentation.
“I believe the paper is frequently cited because
Fabry’s disease is one of the more common sphingolipid storage disorders. Numerous investigations
on the pathogenesis of the clinical manifestations6
in this condition
and approaches to the control
1
and therapy of this disorder have been reported.
A review of historical aspects and summary 8
of recent studies on Fabry’s disease is available.”
I. Anderson W. A case of angiokeratoma. Bn’z. I. Dertttatol. I0:t13-17. 1898. (Cited 70 limes since 1955.)
2. F.br~1. Em Beitrag cur Kenntnis der Putpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae).
Arch. Det’matol. Srphi(is 43:187-200. 1898. (Cited 105 times since 1955.)
3. Sweeky C C & Kllonaky a. Fabrys disease: classification as a sphingolipidosis and partial characterization of a novel
gtvcolipid. I. Biol. C/tern. 238:PC3148-50. 1963. (Cited 230 times.)
4. Brady R 0. Sptsingolipidoses. N. Engi. I. Med. 275:312-18. 1966. (Cited 110 times.)
5. Brid~R 0, Gil A E. Bradley B M & Manen,són E. The metabolism of ceramide trihexosides. I.
Purification and properties of an enzyme that cleaves the terminal galactose molecule of
galactosvtgalactosylgtucosvtceramide. .1, Biol. C/tens. 242:1021-6. 1967. (Cited 75 times.)
6. Brid~8 0. Ultlendort B W & Jacobson C B. Fabrys disease: antenatal diagnosis.
Science 172:174-S. 1971. (Cited 90 times.)
7. Brady R th Tiliman J F. Johnson W G Gal A E Leahy W E, Quirk I M & Dekaban A S. Replacement therapy tor
inherited enryme deliciencv: use of purified ceramidetrihexosidase in Fabrys disease.
N. EngI. J. Med. 289:9-14. 1973. (Cited 120 times.(
8. Brady R 0. Fabr s disease. (Dyck P2. Thomas P K. Lumbers E H & Bange R. cdx.) Peripheral neuroparltv.
Philadelphia: Saunders. 1984. p. 1717-27.
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